Endometriosis is the ectopic presence of endometrial type glands and stroma in sites which are outside of the uterus. This ectopic occurrence of endometrial tissue frequently forms cysts containing altered blood. The condition results in debilitating pain for millions of women worldwide and particularly occurs in conjunction with the monthly proliferation of endometrial tissue. It is frequently a lifelong condition, sometimes associated with infertility.
Endometriosis can be treated by a variety of medical therapies but none of these are sufficiently safe or effective for a long term treatment beyond six months or more. Perhaps the oldest therapy with a demonstrable effect is the administration of progestin either by injection, orally or in combination with oral contraceptives. However, long term administration of progestins have been associated with a number of undesirable side effects, as well as questionable efficacy, and has not received regulatory approval in the U.S.
A synthetic steroid derived from ethisterone, namely 17-.alpha.-pregna-2,4-dien-20-yno[2,3-d]-isoxazol-17-ol, also known as danazol and marketed under the trademark Danocrine has been shown an effective medication for the treatment of endometriosis producing a hypoestrogenic milieu. Unfortunately, this drug also has many androgenic side effects. In addition to the vasomotor flush of estrogen deprivation, it causes weight gain, muscle cramps, breast atrophy, hot flashes, mood swings, oily skin, depression, edema, acne, fatigue, hirsutism, alterations in the libido, headache, rash and a deepening of the voice.
One of the most effective treatments of endometriosis is the administration of a gonadotropin releasing hormone (GnRH) agonist to suppress pituitary gonadotropin secretion and thereby induce a state of reversible pseudomenopause, i.e. administration of a down regulating dose. Although individual response varies, the endometriotic lesions associated with endometriosis usually quickly regress and decrease in size within only three months of initiation of therapy. On withdrawal of the treatment, pain often returns and the endometriosis reappears within a few months after the return of normal menstrual cycles. The drug can also be used to treat fibroid tumors (leiomyomata).
The main drawback of this therapy long-term is a series of side effects stemming from protracted severe hypoestrogenism or the pseudomenopausal state induced by severe estrogen deprivation, namely hot flashes, bone loss and loss of cardiovascular protection by estrogen. While individual response again varies, the bone loss generally begins to be measurable after about 3 months of therapy and sometimes becomes highly significant after about 6 months of therapy in the most vulnerable patients. This bone loss side effect is totally unacceptable from a risk-benefit point of view--the life expectancy after a post-menopausal woman experiences a break of the hip bones due to osteoporosis is only about 3.2 years. Because of this side effect, the U.S. Food & Drug Administration contraindicates any administration of a gonadotropin releasing hormone analog after six months of total administration has elapsed. In other words, the drug cannot be readministered after a resting period according to FDA labelling requirement.
Thus, a matter of concern in GnRH agonist therapy is based on the recognition that prolonged hypoestrogenic status among women of reproductive age can result in cumulative estrogen-depletion side-effects, especially accelerated bone density loss, potentially cumulating in a heightened risk of osteoporosis and bone fractures. Patients receiving a "down regulating" dose of GnRH agonist have grossly deficient estrogen levels rivaling post-menopausal conditions. These concerns have motivated clinical studies of "add back" regimens based on an "estrogen threshold hypothesis" in which patients presented with clinically significant uterine fibroids have used GnRH agonist medications in combination with low dose estrogen-progestin hormone replacement therapy, the latter being similar to the familiar post-menopausal treatment regimes. The object has been to achieve a sufficient reduction in endogenous ovarian estrogen secretion by means of the agonist together with a low dose exogenous estrogen-progestin supplement so that the clinical benefits will not be forfeited due to the "add back" hormone replacement therapy regimen.
The scientific literature also describes the potential use of gonadotropin releasing hormone antagonists as efficacious in the clinical management of endometriosis and uterine leiomyomata. For example, Gordon et al., Suppression of Ovarian Estradiol Secretion by a Single Injection of Antide in Monkeys Follicular Phase: Intermediate, Sustained and Reversible Actions, J. Clin. Endocrin. Metab., 73:1262 (1991), examined the effects of the GnRH antagonist antide and the authors concluded that the antagonist, when administered as a sufficient single dose, could induce immediate and sustained inhibition of the pituitary-ovarian axis. The hypoestrogenic milieu produced was sufficient to expect that management of patients would provide control of various gonadal-steroid dependent conditions, such as endometriosis and leiomyomata uteri, without the delay and potential consequences of the familiar flare and down-regulation response to initiations of GnRH agonist therapy. However, the authors also indicated that a formulation which would give a greater control of bioavailability and, in turn, less individualism of response was highly desirable.
The basis for the antagonist approach of the present invention derives from the recognition that unlike the agonist products, which act by complete inhibition through down regulation of the GnRH receptor system, the antagonist monopolizes the GnRH receptors by competitive occupancy thereby achieving differential degrees of inhibition that are dose dependent. Therefore, it is possible, with the appropriate dose of the GnRH antagonist, to maintain tonic ovarian estradiol secretion at a modest level which is sufficiently reduced to control the estrogen-dependent gynecological problems such as endometriosis but still high enough to avoid the long term sequelae of frank estrogen deficiency.
There is a need to provide a dose and/or regimen of GnRH antagonist which will provide an optimized level of estrogen serum concentration. As noted in the Gordon et al. article referred to above, the response to a particular GnRH antagonist varies from individual to individual. Therefore, the GnRH antagonist dosage must be adjusted in each individual in order to achieve the appropriate degree of estrogen secretion. Accordingly, there is also a need for a convenient method to determine whether an appropriate estrogen level has been established.
It will thus be appreciated that there are a number of therapeutic regimens in which it is desirable to maintain tonic ovarian estrogen secretion. Treatment of endometriosis and leiomyomata are examples. There is a level of agent which is appropriate to safe (i.e. avoidance of menopausal side effect such as bone density loss) and effective (i.e., treatment of the disease state) long-term therapeutic management of gonadal-steroid dependent conditions. The present invention provides that level and a way to establish it.